Phosphate Depletion: A Novel Trigger for Mycobacterium tuberculosis Persistence
Phosphate Depletion: A Novel Trigger for Mycobacterium tuberculosis Persistence
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DOI：
10.1086/605700
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发表时间：
2009-10-01
影响因子：
6.4
通讯作者：
Karakousis, Petros C.
中科院分区：
文献类型：
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作者：
Rifat, Dalin;Bishai, William R.;Karakousis, Petros C.
持久性结核分枝杆菌（MTB）可能会遇到一个磷酸盐限制的巨噬细胞吞噬体内的环境。我们研究了结核分枝杆菌生长，抗生素敏感性，和基因表达在磷酸盐限制。使用磷酸盐相关基因缺陷的MTB突变体，我们评估了在磷酸盐限制条件下以及在小鼠和豚鼠肺中的杆菌存活。磷酸盐限制以剂量依赖性方式限制MTB生长，并且磷酸盐饥饿的杆菌变得对异烟肼表型耐受。磷酸盐饥饿后MTB基因ppk 1和relA显著上调，与无机多磷酸盐积累和MTB严格响应诱导一致。磷酸盐特异性转运操纵子pstS 3-pstC 2-pstA 1在磷酸盐饥饿期间被诱导，其表达依赖于2组分调节系统SenX 3-RegX 3。MTB基因regX 3似乎是磷酸盐限制期间和哺乳动物肺中的杆菌存活所必需的。我们的数据表明，结核分枝杆菌遇到磷酸盐限制的条件下，在哺乳动物肺部感染和磷酸盐饥饿反应（PSR）的表达是重要的结核分枝杆菌的持久性。
Persistent Mycobacterium tuberculosis (MTB) likely encounters a phosphate-limited environment within macrophage phagosomes. We studied MTB growth, antibiotic susceptibility, and gene expression during phosphate limitation. With use of MTB mutants deficient in phosphate-related genes, we assessed bacillary survival under phosphate-limited conditions and in mouse and guinea pig lungs. Phosphate limitation restricted MTB growth in a dose-dependent manner, and phosphate- starved bacilli became phenotypically tolerant to isoniazid. The MTB genes ppk1 and relA were upregulated significantly after phosphate starvation, consistent with inorganic polyphosphate accumulation and MTB stringent response induction. The phosphate- specific transport operon pstS3-pstC2-pstA1 was induced during phosphate starvation and its expression was dependent on the 2-component regulatory system SenX3-RegX3. The MTB gene regX3 appears to be essential for bacillary survival during phosphate limitation and in mammalian lungs. Our data suggest that MTB encounters phosphate-limited conditions during mammalian lung infection and that expression of the phosphate starvation response (PSR) is important for MTB persistence.